Impaired BK(Ca) channel function in native vascular smooth muscle from humans with type 2 diabetes

Large-conductance Ca(2+)-activated potassium (BK(Ca)) channels are key determinants of vascular smooth muscle excitability. Impaired BK(Ca) channel function through remodeling of BK(Ca) β1 expression and function contributes to vascular complications in animal models of diabetes. Yet, whether similar alterations occur in native vascular smooth muscle from humans with type 2 diabetes is unclear. In this study, we evaluated BK(Ca) function in vascular smooth muscle from small resistance adipose arteries of non-diabetic and clinically diagnosed type 2 diabetic patients. We found that BK(Ca) channel activity opposes pressure-induced constriction in human small resistance adipose arteries, and this is compromised in arteries from diabetic patients. Consistent with impairment of BK(Ca) channel function, the amplitude and frequency of spontaneous BK(Ca) currents, but not Ca(2+) sparks were lower in cells from diabetic patients. BK(Ca) channels in diabetic cells exhibited reduced Ca(2+) sensitivity, single-channel open probability and tamoxifen sensitivity. These effects were associated with decreased functional coupling between BK(Ca) α and β1 subunits, but no change in total protein abundance. Overall, results suggest impairment in BK(Ca) channel function in vascular smooth muscle from diabetic patients through unique mechanisms, which may contribute to vascular complications in humans with type 2 diabetes.